Novel crystalline forms of aripiprazole

ABSTRACT

The present invention provides novel crystalline forms of aripiprazole and aripiprazole hydrochloride, processes for their preparation and pharmaceutical compositions containing them.

FIELD OF THE INVENTION

The present invention provides novel crystalline forms of aripiprazoleand aripiprazole hydrochloride, processes for their preparation andpharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Aripiprazole of formula (1):

or7-[4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinoneand its salts are useful for treating schizophrenia and theirtherapeutic uses were disclosed in U.S. Pat. No. 5,006,528.

Processes for the preparation of aripiprazole and its salts weredescribed in U.S. Pat. No. 5,006,528. These processes do not producewell defined, reproducible crystalline forms.

Thus there is a need for stable and reproducible crystalline forms ofaripiprazole and its salts.

We have discovered two novel crystalline forms of aripiprazole and fournovel crystalline forms of aripiprazole hydrochloride. The novel formshave been found to be stable over the time and reproducible and so,suitable for pharmaceutical preparations.

Thus, the object of the present invention is to provide stable novelcrystalline forms of aripiprazole, processes for preparation of thenovel crystalline forms and pharmaceutical compositions containing thesenovel crystalline forms.

Another object of the present invention is to provide stable novelcrystalline forms of aripiprazole hydrochloride, processes forpreparation of the novel crystalline forms and pharmaceuticalcompositions containing these novel crystalline forms.

Since the novel crystalline forms of aripiprazole hydrochloride areobtained with high purity, preparation of aripiprazole via thecrystalline forms of aripiprazole hydrochloride serves as a means ofproducing pure aripiprazole.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided anovel crystalline form of aripiprazole, designated as Form I,characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 8.7, 11.6, 16.3, 17.7, 18.6, 20.3, 23.4, 24.9degrees. FIG. 1 shows typical Form I x-ray powder diffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form I of aripiprazole comprising thesteps of:

-   -   a) dissolving aripiprazole in a suitable solvent;    -   b) refluxing for about 30 minutes to 1 hour;    -   c) cooling slowly to about 15° C. to 25° C.;    -   d) maintaining for about 2 hour to 4 hours at about 15° C. to        25° C.; and    -   e) filtering the solid separated.

The suitable solvent is selected from the group consisting of acetone,ethyl acetate, methanol or ethanol.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole, designated as Form II,characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 12.7, 15.1, 17.5, 18.2, 18.8, 19.5, 20.6, 21.2,22.6, 23.3, 24.2, 24.9, 27.6, 30.0, 31.6, 35.8 degrees. FIG. 2 showstypical Form II x-ray powder diffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form II of aripiprazole, which comprisesdissolving aripiprazole in tetrahydrofuran and vacuum drying at about25° C. or spray drying.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole hydrochloride, designated asForm A, characterized by an x-ray powder diffraction pattern havingpeaks expressed as 2θ at about 6.2, 8.5, 11.5, 15.2, 15.5, 16.8, 17.2,18.3, 18.9, 19.6, 20.6, 21.3, 23.4, 24.1, 24.7, 25.9, 27,5, 28.3, 28.9,32.8 degrees. FIG. 3 shows typical Form A x-ray powder diffractionpattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form A of aripiprazole hydrochloridecomprising the steps of:

-   -   a) dissolving aripiprazole in methanol or isopropyl alcohol;    -   b) adding hydrochloric acid;    -   c) maintaining for about 1 hour to 3 hours at about 15° C. to        25° C.;    -   d) filtering the solid separated.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole hydrochloride, designated asForm B, characterized by an x-ray powder diffraction pattern havingpeaks expressed as 2θ at about 9.3, 14.8, 16.4, 17.4, 18.7, 19.7, 21.4,21.9, 23.8, 25.1, 25.9, 29.7 degrees. FIG. 4 shows typical Form B x-raypowder diffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form B of aripiprazole hydrochloridecomprising the steps of:

-   -   a) dissolving aripiprazole in a ketonic solvent;    -   b) adding hydrochloric acid;    -   c) maintaining for about 1 hour to 4 hours at about 15° C. to        25° C.;    -   d) filtering the solid separated.        The ketonic solvent is selected from the group consisting of        acetone, methyl isobutyl ketone and methyl ethyl ketone.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole hydrochloride, designated asForm C, characterized by an x-ray powder diffraction pattern havingpeaks expressed as 2θ at about 3.3, 10.3, 14.2, 14.6, 15.1, 16.4, 16.6,19.4, 20.3, 20.8, 24.5, 24.9, 25.5, 26.4, 26.7, 28.5, 29.3, 30.1degrees. FIG. 5 shows typical Form C x-ray powder diffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form C of aripiprazole hydrochloridecomprising the steps of:

-   -   a) dissolving aripiprazole in an ester solvent;    -   b) adding hydrochloric acid;    -   c) maintaining for about 1 hour to 4 hours at about 15° C. to        25° C.;    -   d) filtering the separated solid.        The ester solvent is selected from the group consisting of ethyl        acetate, methyl acetate, ethyl formate and tert-butyl acetate.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole hydrochloride, designated asForm D, characterized by an x-ray powder diffraction pattern havingpeaks expressed as 2θ at about 9.0, 14.7, 16.4, 17.4, 19.0, 19.3, 19.8,21.4, 23.4, 24.7, 25.4 degrees. FIG. 6 shows typical Form D x-ray powderdiffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form D of aripiprazole hydrochloridecomprising the steps of:

-   -   a) dissolving aripiprazole in tetrahydrofuran;    -   b) adding hydrochloric acid;    -   c) maintaining for about 2 hour to 4 hours at about 15° C. to        25° C.;    -   d) filtering the solid separated.

According to another aspect of the present invention there is provided apharmaceutical composition comprising crystalline Form I or Form II ofaripiprazole.

According to another aspect of the present invention there is provided apharmaceutical composition comprising novel crystalline form ofaripiprazole hydrochloride.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a x-ray powder diffraction pattern of crystalline Form I ofaripiprazole.

FIG. 2 is a x-ray powder diffraction pattern of crystalline Form II ofaripiprazole.

FIG. 3 is a x-ray powder diffraction pattern of crystalline Form A ofaripiprazole hydrochloride.

FIG. 4 is a x-ray powder diffraction pattern of crystalline Form B ofaripiprazole hydrochloride.

FIG. 5 is a x-ray powder diffraction pattern of crystalline Form C ofaripiprazole hydrochloride.

FIG. 6 is a x-ray powder diffraction pattern of crystalline Form D ofaripiprazole hydrochloride.

x-Ray powder diffraction spectrum was measured on a Siemensdiffractometer.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect of the present invention, there is provided anovel crystalline form of aripiprazole, designated as Form I,characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 8.7, 11.6, 16.3, 17.7, 18.6, 20.3, 23.4, 24.9degrees. FIG. 1 shows typical Form I x-ray powder diffraction pattern.

According to another aspect of the present invention, there is provideda process for preparation of the Form I of aripiprazole. Thusaripiprazole is dissolved in a suitable solvent. The suitable solvent isselected from the group consisting of acetone, ethyl acetate, methanoland ethanol. Aripiprazole obtained by a known method or crystalline FormII of aripiprazole obtained by the process described below may be used.The solution is refluxed for about 30 minutes to 1 hour. The solution isthen cooled slowly to about 15° C. to 25° C. in about 1 hour andmaintained for about 2 hour to 4 hours at the same temperature. Theseparated crystals are filtered and dried to give Form I ofaripiprazole.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole, designated as Form II,characterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 12.7, 15.1, 17.5, 18.2, 18.8, 19.5, 20.6, 21.2,22.6, 23.3, 24.2, 24.9, 27.6, 30.0, 31.6, 35.8 degrees. FIG. 2 showstypical Form II x-ray powder diffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form II of aripiprazole, which comprisesdissolving aripiprazole in tetrahydrofuran and vacuum drying at about25° C. or spray drying.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole hydrochloride, designated asForm A, characterized by an x-ray powder diffraction pattern havingpeaks expressed as 2θ at about 6.2, 8.5, 11.5, 15.2, 15.5, 16.8, 17.2,18.3, 18.9, 19.6, 20.6, 21.3, 23.4, 24.1, 24.7, 25.9, 27,5, 28.3, 28.9,32.8 degrees. FIG. 3 shows typical Form A x-ray powder diffractionpattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form A of aripiprazole hydrochloride.Thus aripiprazole is dissolved in ethanol or isopropyl alcohol. Ifnecessary, the solvent may be heated to effect dissolution ofaripiprazole. Hydrochloric acid is added to the solution. Hydrochloricacid may be added as an aqueous solution or as a solution in any othersolvent; or hydrochloric acid gas may be passed through the solution ofaripiprazole. Then the contents are maintained for about 1 hour to 3hours at about 15° C. to 25° C. and the separated crystals are filteredand dried to yield Form A of aripiprazole hydrochloride.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole hydrochloride, designated asForm B, characterized by an x-ray powder diffraction pattern havingpeaks expressed as 2θ at about 9.3, 14.8,16.4, 17.4,18.7, 19.7, 21.4,21.9, 23.8, 25.1, 25.9, 29.7 degrees. FIG. 4 shows typical Form B x-raypowder diffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form B of aripiprazole hydrochloride.Thus aripiprazole is dissolved in a ketonic solvent. If necessary, thesolvent may be heated to dissolve aripiprazole. The ketonic solvent isacetone or methyl isobutyl ketone or methyl ethyl ketone; or mixturethereof. Hydrochloric acid is added to the solution. Hydrochloric acidmay be added as an aqueous solution or as a solution in any othersolvent; or hydrochloric acid gas may be passed through the solution ofaripiprazole. Then the contents are maintained for about 1 hour to 4hours at about 15° C. to 25° C. and the separated crystals are filteredand dried to yield Form B of aripiprazole hydrochloride.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole hydrochloride, designated asForm C, characterized by an x-ray powder diffraction pattern havingpeaks expressed as 2θ at about 3.3, 10.3, 14.2, 14.6, 15.1, 16.4, 16.6,19.4, 20.3, 20.8, 24.5, 24.9, 25.5, 26.4, 26.7, 28.5, 29.3, 30.1degrees. FIG. 5 shows typical Form C x-ray powder diffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form C of aripiprazole hydrochloride.Thus aripiprazole is dissolved in an ester solvent. If necessary, thesolvent may be heated to effect dissolution of aripiprazole. The estersolvent is selected from the group consisting of ethyl acetate, methylacetate, ethyl formate and tert-butyl acetate. Hydrochloric acid isadded to the solution. Hydrochloric acid may be added as an aqueoussolution or as a solution in any other solvent; or hydrochloric acid gasmay be passed through the solution of aripiprazole. Then the contentsare maintained for about 1 hour to 4 hours at about 15° C. to 25° C. andthe separated solid is filtered and dried to obtain Form C ofaripiprazole hydrochloride.

According to another aspect of the present invention, there is provideda novel crystalline form of aripiprazole hydrochloride, designated asForm D, characterized by an x-ray powder diffraction pattern havingpeaks expressed as 2θ at about 9.0, 14.7, 16.4, 17.4, 19.0, 19.3, 19.8,21.4, 23.4, 24.7, 25.4 degrees. FIG. 6 shows typical Form D x-ray powderdiffraction pattern.

According to another aspect of the present invention there is provided aprocess for preparation of the Form D of aripiprazole hydrochloride.Thus aripiprazole is dissolved in tetrahydrofuran. Hydrochloric acid isadded to the solution. Hydrochloric acid may be added as an aqueoussolution or as a solution in any other solvent; or hydrochloric acid gasmay be passed through the solution of aripiprazole. Then the contentsare maintained for 2 hour to 4 hours at about 15° C. to 25° C. and theseparated crystals are filtered and dried to produce Form D ofaripiprazole hydrochloride.

The novel crystalline forms of aripiprazole hydrochloride obtained bythe processes described above are very pure. So, aripiprazole with highpurity can be obtained by basifying a solution of aripiprazolehydrochloride crystalline form and isolating aripiprazole from thesolution by usual processes known in the art.

According to another aspect of the present invention there is provided apharmaceutical composition comprising Form I or Form II of aripiprazoleand a pharmaceutically acceptable carrier.

According to another aspect of the present invention there is provided apharmaceutical composition comprising crystalline form of aripiprazolehydrochloride and a pharmaceutically acceptable carrier. The crystallineform may be Form A, Form B, Form C or Form D.

The forms of aripiprazole or aripiprazole hydrochloride may beformulated in a form suitable for oral administration or injection. Theexamples of pharmaceutical compositions are tablets, capsules, powders,suspensions, emulsions, injections and the like.

The following examples will serve to further illustrate the invention.

EXAMPLE 1

Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No.5,006,528) is dissolved in acetone (42 ml) and refluxed for 30 minutes.The solution is slowly cooled to 25° C. in 1 hour and maintained at 25°C. for 3 hours. The separated crystals are filtered and dried to give 1gm of Form I of aripiprazole.

EXAMPLE 2

Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No.5,006,528) is dissolved in tetrahydrofuran and the solvent is removed byvacuum drying at 25° C. for 6 hours to give Form II of aripiprazole inquantitative yield.

EXAMPLE 3

Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No.5,006,528) is dissolved in tetrahydrofuran and the solvent is removed byspray drying at 25° C. for 6 hours to give Form II of aripiprazole inquantitative yield.

EXAMPLE 4

Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No.5,006,528) is dissolved in methanol (12 ml) and conc. hydrochloric acid(1 ml) is added to the solution. The contents are maintained for 2 hoursat 25° C. and the separated solid is filtered to give 2 gm of Form A ofaripiprazole hydrochloride.

EXAMPLE 5

Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No.5,006,528) is dissolved in acetone (12 ml) and conc. hydrochloric acid(1 ml) is added to the solution. The contents are maintained for 3 hoursat 25° C. and the separated solid is filtered to give 1.9 gm of Form Bof aripiprazole hydrochloride.

EXAMPLE 6

Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No.5,006,528) is dissolved in ethyl acetate (12 ml). 10% W/V HCl in ethylacetate (4 ml) is added to the solution. The solution is maintained at25° C. for 2 hours and the separated crystals are collected byfiltration to give 2 gm of Form C of aripiprazole hydrochloride.

EXAMPLE 7

Aripiprazole (2 gm) (obtained by a process described in U.S. Pat. No.5,006,528) is dissolved in tetrahydrofuran (12 ml) and conc.hydrochloric acid (1 ml) is added to the solution. The contents aremaintained for 3 hours at 25° C. and the separated solid is collected byfiltration to give 2 gm of Form D of aripiprazole hydrochloride.

EXAMPLE 8

Example 1 is repeated using Form II of aripiprazole instead ofaripiprazole to give Form I of aripiprazole.

EXAMPLE 9

Example 2 is repeated using Form I of aripiprazole instead ofaripiprazole to give Form II of aripiprazole.

EXAMPLE 10

Example 5 is repeated using Form I of aripiprazole instead ofaripiprazole to give Form B of aripiprazole hydrochloride.

EXAMPLE 11

Example 7 is repeated using Form II of aripiprazole instead ofaripiprazole to give Form D of aripiprazole hydrochloride.

1-18. (canceled)
 19. A crystalline Form C of aripiprazole hydrochloridecharacterized by an x-ray powder diffraction pattern having peaksexpressed as 2θ at about 3.3, 10.3, 14.2, 14.6, 15.1, 16.4, 16.6, 19.4,20.3, 20.8, 24.5, 24.9, 25.5, 26.4, 26.7, 28.5, 29.3, 30.1 degrees. 20.A crystalline aripiprazole hydrochloride, characterized by an x-raypowder diffraction pattern as in FIG.
 5. 21. A process for preparationof Form C of aripiprazole hydrochloride of claim 19, comprising thesteps of: a) dissolving aripiprazole in an ester solvent; b) addinghydrochloric acid; c) maintaining for about 1 hour to 4 hours at about15° C. to 25° C.; and d) filtering the separated solid; wherein theester solvent is selected from the group consisting of ethyl acetate,methyl acetate, ethyl formate and tert-butyl acetate.
 22. A processaccording to claim 21, wherein the ester solvent is ethyl acetate.
 23. Aprocess according to claim 21, wherein the ester solvent is methylacetate.